The central focus of this project is to define the signaling pathways that lead from sarcomere gene mutation to hypertrophic cardiomyopathy, dilated cardiomyopathy, dilated cardiomyopathy and/or heart failure. During the previous grant period we demonstrated that mutations in sarcomere protein genes cause familial hypertrophic cardiomyopathy (FHC). Many, if not all, FHC-causing mutations, create poison polypeptides that become incorporated into the growing sarcomere and create defective sarcomeres. However, we do not understand how these defective sarcomeres lead to dramatic changes in cardiac morphology and function. Some individuals bearing these mutations can live for many years without demonstrating any clinical signs of disease, while others develop disease symptoms early in childhood. To create tools to study these signaling pathways we have create two lines of mice; each line of mice bears a mutation that causes FHC in man. One line bears the Arg403Gln mutation in the alpha-cardiac myosin heavy chain gene, and the other line bears a truncation mutation in the cardiac myosin binding protein C gene. Heterozygous mice bearing these mutations develop features of FHC, whole homozygous mice bearing these mutations develop dilated cardiomyopathy and in one case, heart failure. We propose a series of experiments that should define the signaling pathways activated in these sarcomere defective mice. Specifically we propose to: 1) Identify molecules involved in the pathways that lead to dilated cardiomyopathy in MyBPC T/T mice and alphaMHC/403/403 mice. 2) Identify molecules in the pathways that lead to cardiac hypertrophy in heterozygous MyBPC/T/+ mice and alphaMHC/403/+ MICE. 3) Assess the mechanisms by which cyclosporin induces rapid development of cardiac hypertrophy in sarcomere protein gene mutant bearing mice. 4) Define the phenotype of compound heterozygous MyBPC/T/+ mice and alphaMHC/403/+ mice. 5) Assess treatment phenotype of compound heterozygous MyBPC/T/+ mice and alphaMHC403/+ mice. 5) Assess treatment modalities and environmental factors that affect the cardiac response to sarcomere protein gene mutations. During the past few years we, in collaboration with other projects and Core facilities supported by this SCOR center, have developed the methods necessary to characterize these murine models. In particular, we have benefitted from associated with Core B which provide echocardiographic facilities which are essential for evaluation of mouse cardiac structure and Core C which performed histologic analysis which are a significant part of phenotype analyses. Further, our choice of disease gene models came from studies performed in collaboration with project 1. The analysis of cardiac function were originally conducted in collaboration with Dr. Ingwall. In the next granting period we, in collaboration with projects 3 (Dr. Ingwall) and 4 (Dr. Neer) will evaluate further these mutant mice using expertise and equipment available in the Core facilities. In summary, we propose to continue our efforts to define the signaling pathways that lead to and from sarcomere protein gene mutation to dilated cardiomyopathy, FHC and heart failure. We recognize that these studies will receive significant benefits from our close association with the SCOR center.